1. Field of the Invention
The present invention relates to a TNF-xcex1 production inhibitor containing a kavalactone as an active ingredient, and to a preventive, ameliorating, or therapeutic agent for diseases caused by abnormal production of TNF-xcex1.
2. Background Art
TNF (Tumor Necrosis Factor) was discovered as an antitumor cytokine, and has been elucidated to have carcinostatic activity (i.e., the effect of inhibiting cancer cell growth or necrotizing cancer cells), and to participate in a series of inflammatory responses or immunoreactions, as well as in differentiation or maturation of cells.
Recent studies have shown that excessive production of TNF-xcex1 induces onset of a variety of diseases, including cachexia attributed to cancer or infectious diseases (Nature, 316: 552, 1985), septic shock (J. Immunol., 145: 4185, 1990; Science, 229: 869, 1985; Shock, 30: 1990), chronic rheumatoid arthritis (Ann. Rheum. Dis., 49: 665, 1990; Lancet, 344: 1105, 1994; Lancet, 344: 1125, 1994; British J. Rheum., 34: 334, 1995), inflammatory diseases such: as ulcerative colitis and Crohn disease (Arch. Dis. Child, 66: 561, 1991; Gastroenterology), osteoarthritis (Arthritis Rheum., 36: 819, 1993), Kawasaki""s disease (Clin. Immunol. Immunopathol., 56: 29, 1990), multiple sclerosis (N. Engl. J. Med., 325(7): 467, 1991), Behchet""s disease (J. Rheumatol., 17: 1107, 1990), systemic lupus erythematosus (SLE) (Arthritis Rheum., 32: 146, 1989), rejection during bone marrow transplantation (J. Exp. Med., 175: 405, 1992), multiple organ failure (Rinshoi, 17(20), 2006, 1991), malaria (Science, 237: 1210, 1987), AIDS (J. Acquir. Immune Defic. Syndr., 5: 1099, 1992), meningitis (Lancet, 1: 355,1987), hepatitis (Kozo Kanno, Kanzo, 33: 213, 1992), and type-II diabetes (Science, 259: 87, 1993).
The aforementioned diseases caused by excessive production of TNF-xcex1 have hitherto been treated from a mere palliative approach by use of steroid agents, anti-inflammatory agents, antibiotics, etc., and drugs for fundamentally treating the diseases have not yet been developed.
Kava is a plant found in Fiji and belongs to Piperaceae, Piper L. (nomenclature: Piper Methysticum Forst., alias: Yangona). Since anesthetic beverages are obtained from the kava root, in Oceania, kava is widely cultivated by privileged people and is used in traditional ceremonies or events (Chem. Australia. Oct 377-378 (1987)).
It has been reported that an extract obtained from the dried kava root through extraction with water contains a class of xcex1-pyrone derivatives called kavalactones which induce numbness of the lips or tongue or exert sedative effect, such as methysticin (Chem. Australia. Oct 377-378 (1987), Planta Med. 64 504-506 (1998)).
Studies performed in the University of New South Wales have elucidated that kavalactones exert a sedative effect through a mechanism different from those of other sedative drugs which exert sedative effects when being bound to receptors present in the brain (Planta Med. 64 507-510 (1998)). It has also been reported that kavalactones exert an analgesic effect in a manner different from that of a formulated analgesic drug such as aspirin, and that, unlike morphine, kavalactones are not bound to receptors in the brain (e.g., European Patent Application Laid-Open Nos. 664131 and 523591, and Japanese Kdhyo (PCT) Patent Publication No. 5-502457).
It has also been reported that kava extract exerts an antibacterial effect and is useful for treating Helicobacter pylori infection (German Patent Application Laid-Open No. 19716660), and that the kava extract exerts a neuroprotective effect and is useful for treating brain dysfunction, Alzheimer""s disease, brain injury, etc. (e.g., European Patent Application Laid-Open No. 523591, and Japanese Kohyo (PCT) Patent Publication No. 5-502457).
However, until the present invention was attained, kavalactones and kava extract have not been known to exert the effect of inhibiting TNF-xcex1 production.
In view of the foregoing, the present inventors have performed studies on naturally occurring substances which inhibit production of TNF-xcex1, and have found that kavalactones contained in kava extract exert an excellent effect of inhibiting TNF-xcex1 production, and that the kavalactones are useful as TNF-xcex1 production inhibitors and as preventive, ameliorating, or therapeutic agents for a variety of diseases caused by abnormal production of TNF-xcex1. The present invention has been accomplished on the basis of this finding.
Thus, an object of the present invention is to provide a drug which is endowed with high safety, inhibits TNF-xcex1 production, and is useful as a preventive or therapeutic agent for the aforementioned diseases.
Accordingly, the present invention provides a TNF-xcex1 production inhibitor comprising a kavalactone as an active ingredient.
The present invention also provides a preventive, ameliorating, or therapeutic agent comprising a kavalactone as an active ingredient for diseases caused by abnormal production of TNF-xcex1.
The present invention further provides a method for the treatment of diseases caused by abnormal production of TNF-xcex1, which method comprises administering an effective amount of a kavalactone.
The present invention further provides use of a kavalactone for the manufacture of a TNF-xcex1 production inhibitor.
Still, the present invention provides use of a kavalactone for the manufacture of a medicament for preventing, ameliorating, or treating diseases caused by abnormal production of TNF-xcex1.
Preferably, the kavalactone is one or more species selected from the group consisting of desmethoxyyangonin, dihydrokavain, kavain, yangonin, methysticin, dihydromethysticin, and 7,8-epoxyyangonin.